Dementia is a widely-recognized and very serious health problem. Alzheimer's disease accounts for more than 50% of the dementia in the elderly, and it is also a major cause of death in Americans over age 65. Four million Americans, and 40% of those over age 85 (the fastest growing segment of the U.S. population), have Alzheimer's disease. Twenty-five percent of all patients with Parkinson's disease also suffer from a dementia similar to that seen in Alzheimer's disease. And in about 15% of patients with dementia, Alzheimer's disease and multi-infarct dementia coexist. The third most common dementia, after Alzheimer's disease and vascular dementia, is cognitive impairment due to organic brain disease related directly to alcoholism, which occurs in about 10% of alcoholics.
The precise molecular lesions causing the morphological and functional deficits associated with dementia are not known, despite intensive research efforts over the last decade. However, the most consistent abnormality for Alzheimer's disease is the degeneration of the cholinergic system arising from the basal forebrain (BF) to both the cortex and hippocampus. This is also seen in vascular dementia and cognitive impairment due to organic brain disease related to alcoholism (Bigl et al., in Brain Cholinergic Systems, M. Steriade and D. Biesold, eds., Oxford University Press, Oxford, 1990, pp. 364-386). In particular, decreases in markers of cholinergic neuronal function are seen in brains of patients afflicted with Alzheimer's disease (Perry et al., Br. Med. J., 1978, 2:1457; Reisine et al., Brain Res., 1978, 159:477; Coyle et al., Science, 1983, 219:1184; and McGeer et al., Neurology, 1984, 34:741). There are a number of other neurotransmitter systems affected by Alzheimer's disease (Davies, Med. Res. Rev., 1983, 3:221). However, these are relatively less profound than the decreases in these cholinergic neuronal function markers.
Substantial reductions (30-50%) in nicotinic cholinergic channel receptors have been consistently reported in the brains of patients with Alzheimer's disease or Parkinson's disease (Kellar et al., Brain Res., 1987, 436:62; and Whitehouse et al., Neurol., 1988, 38:720), whereas changes in muscarinic cholinergic receptors are less remarkable and more dependent on receptor subtype.
Degeneration of the cholinergic neurotransmitter system is also seen in otherwise-healthy aged adults and rats. Decreases in cholinergic markers in the basal forebrain, decreases in cortical activities of the biosynthetic and degradative enzymes for acetylcholine, decreases in the ability to release acetylcholine from tissue slices, and decreases in numbers of cortical nicotinic cholinergic channel receptors have all been reported in such otherwise-healthy aged individuals (for a review, see Giacobini, J. Neurosci. Res., 1990, 27:548). Moreover, for those cholinergic neurons that remain, aging may cause a decrease in the temporal fidelity of existing impulse flow from the basal forebrain to the cortex (Aston-Jones et al., Brain Res.,1985, 325:271). These findings are consistent with pharmacological studies suggesting that cholinergic mechanisms are also, at least in part, responsible for the memory disturbances in aged animals and humans not suffering from Alzheimer's disease (Drachman and Leavitt, Arch. Neurol., 1974, 30:113; and Bartus et al., Science, 1982, 217:408).
Other clinical symptoms that correlate with the neurodegenerative process of Alzheimer's disease include decreases in regional cerebral blood flow and cerebral glucose utilization in regions which largely parallel the areas where cholinergic deficits occur (Ingvar and Risberg, Exp. Brain Res., 1962, 3:195; Ingvar et al., in Aging: Alzheimer's Disease, Senile Dementia and Related Disorders, Vol. 7, R. Katzman, R. D. Terry, and K. L. Bick, eds., Raven Press, 1978, p. 203; and Dastur, J. Cerebral Blood Flow & Metabol., 1985, 5:1). In fact, it has been suggested that routine measurement of cerebral blood flow may be a useful procedure in evaluating patients suspected of having dementia, and of having Alzheimer's disease in particular.
Although decreases in cerebral blood flow and cerebral glucose utilization are generally reported in aged populations, it has been suggested that these decreases are secondary to other ongoing cerebral dysfunctions. Nonetheless, deficiencies in metabolic and cerebrovascular responses to pharmacologic and physiologic perturbation are consistently reported. Another recent study has shown that older rats have a smaller increase in cerebral blood flow than younger rats, in response to an electric stimulus to the basal forebrain (Linville and Arneric, Neurobiol. Aging 1991, 12:503). Indeed, in studies that compare the degree of learning impairment to the degree of reduced cortical cerebral blood flow in aged rats a good correlation between the two is seen (Berman et al., Neurobiol. Aging, 1988, 9:691).
Recent clinical evidence suggests that the characteristic perfusion abnormality observed in Alzheimer's disease patients reflects regional nicotinic cholinergic deficits (Prohovnik, Neurobiol. Aging, 1990, 11:262). In particular, mecamylamine, a centrally-acting nicotinic receptor antagonist, reduces resting cortical perfusion in the parietotemporal cortex of humans, the area of the cortex most consistently found to be impaired in functional brain imaging of Alzheimer's disease patients. In agreement with this finding, regulation of cerebral blood flow in the frontoparietal cortex, governed by the basal forebrain, is also dependent upon nicotinic mechanisms in the rat (Arneric, J. Cerebral Blood Flow & Metabol., 1989, 9 (Suppl. 1): S502).
Chronic alcoholism, and more particularly the resultant organic brain disease seen in such patients, is also characterized by diffuse reductions in cortical cerebral blood flow in those brain regions where cholinergic neurons arise (basal forebrain) and to which they project (cerebral cortex) (Lofti & Meyer, Cerebrovasc. and Brain Metab. Rev., 1989, 1:2). Moreover, of all the neurotransmitter systems studied, the neurotoxic effects of alcohol on the cholinergic system are thought to be the most important.
Any therapies directed towards enhancing cognitive processing should therefore be directed to maintaining a well-regulated balance between adequate cerebral blood flow, cerebral glucose utilization and cholinergic neurotransmission arising from the basal forebrain.
Pilot clinical studies suggest that nicotine may be useful for the acute treatment of deficits in attention and information processing associated with Alzheimer's disease (Sahakian et al., Brit. J. Psych., 1989, 154:797; and Newhouse et al., Psychopharmacol., 1988, 95:171). It has been shown that both acutely- and chronically-administered nicotine enhances cognitive function in rats (Levin et al., Behav. Neural Biol., 1990, 53:269), including aged animals (Cregan et al., Soc. Neurosci. Abstract, 1989, 15: 2952). Additionally, anecdotal evidence suggests that people who smoke are less likely to acquire Alzheimer's disease. This is supported by animal studies that demonstrate a neuroregenerative-neuroprotective action of chronically-administered nicotine on both neuronal and vascular functions following hemitransection or MPTP-induced destruction of the nigro-striatal dopamine system (Janson et al., Prog. Brain Res., 1989, 79:257; and Owman et al., Prog. Brain Res., 1989, 79:267). Interestingly, in contrast to the classical down-regulation of receptors typically seen with receptor agonists, chronic nicotine administration up-regulates (50-100%) the number of receptors without affecting affinity (Benwell et al., J. Neurochem., 1988, 50:1243). This effect occurs both in humans and in smaller animals such as rats (Lapchack et al., J. Neurochem., 1989, 52:483).
Although various cholinergic channel agonists have been tested, both nicotine and various muscarinic agents have proven to be therapeutically sub-optimal. Nicotine has an unfavorable pharmacokinetic profile and poor oral bioavailability. The muscarinic agents, including arecoline, carbachol and RS-86, for example, also suffer from various deficiencies, such as has unfavorable pharmacokinetics in the case of arecoline, poor CNS penetration with carbachol, and poor potency and lack of selectivity for CNS receptors with RS-86. RS-86 has similar affinity for muscarinic receptors located in the heart and in cortical tissues and is a full agonist at cardiac receptors, whereas it is only a partial agonist at cortical receptors (S. B. Freedman, Brit. J. Pharmacol., 1986, 87: 29P). In addition, other known cholinergic agents of the muscarinic type have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor, and serious peripheral side effects that including miosis, lacrimation, defecation and tachycardia (Benowitz et al., in Nicotine Psychopharmacology, S. Wonnacott, M. A. H. Russell, & I. P. Stolerman, eds., Oxford University Press, Oxford, 1990, pp. 112-157; and M. Davidson et al., in Current Research in Alzheimer Therapy , E. Giacobini and R. Becker, eds.; Taylor & Francis: New York, 1988; pp 333-336).
An active cholinergic agent of the nicotinic type should be able to treat a decline in cognitive ability by improving cholinergic function and cerebral blood flow. An added advantage would accrue to such a compound that was able to treat the other symptoms that accompany the earlier stages of Alzheimer's disease. One such symptom is anxiety. Anxiolytics have been used to treat the severe agitation that most Alzheimer's patients experience with the initial loss of memory (IN PHARMA, Mar. 16, 1991, pg 20). In fact, the use of anxiolytics has become an important aspect of strategies for treating Alzheimer's disease (Schmidt et al., Drug Dev. Res., 1988, 14:251). Nicotine is known to have anxiolytic properties (Pomerleau et al., Addictive Behaviors, 1984, 9:265). It is to be expected, therefore, that nicotine or selective nicotine agonists may be useful in the treatment of the anxiety associated with dementias, such as Alzheimer's disease.
Other treatment opportunities where enhanced therapeutic benefits may be achieved by administration of nicotine or a cholinergic channel activator of the nicotinic type include attentional deficit disorder and drug withdrawal, which are accompanied by anxiety.
Attention-deficit disorder (ADD), with or without hyperactivity, is a behavioral disorder characterized by distractibility and impulsiveness. Children with this disorder cannot concentrate or control their impulsivity, especially in schooling environments. Some stimulants, for example, pemoline, have been used successfully in management of the behavioral manifestations of ADD. Nicotine is also potentially useful in treating ADD, because of its ability to improve concentration and task performance (F. T. Etscorn, U.S. Pat. No. 4,597,961, issued Jul. 1, 1986; and D. M. Warburton and K. Wesnes in Smoking Behavior, R. E. Thornton, ed., Churchill-Livingston, Edinburgh, 1978, pp. 19-43).
Tobacco use, especially cigarette smoking, has long been recognized as a possible cause of disease and death. Tars, carcinogens, and carbon monoxide are among the compounds in smoke that compromise the health of smokers. The most pharmacologically-active substance in tobacco products is nicotine, which is the reinforcing agent responsible for maintaining tobacco dependency (J. H. Jaffe, in Nicotine Pharmacology: Molecular, Cellular and Behavioral Aspects, S. Wonnacott, M. A. H. Russell and I. P. Stolerman, eds., Oxford Science Publications, Oxford, 1990, pp. 1-37).
As campaigns to encourage people to stop smoking take effect, the nicotine withdrawal syndrome associated with smoking cessation, which is characterized by craving for nicotine, irritability, frustration or anger, anxiety, difficulty in concentrating, restlessness, decreased heart rate, increase in appetite and weight gain, becomes increasingly important. It is not surprising that nicotine been found to ease the withdrawal experienced by those attempting to break tobacco dependencies. As early as 1942, Johnston reported that injections of nicotine relieved the withdrawal symptoms experienced by cigarette smokers when they stopped smoking (Lancet, 1942, 2:742). In recent double-blind studies, nicotine was found to be far superior to a placebo for suppressing or preventing the appearance of many of the signs and symptoms of withdrawal (J. R. Hughes et al., Psychopharmacology, 1984, 83:82-7; N. G. Schneider et al., Addictive Behavior, 1984, 9:149-56; R. J. West et al., Journal of Addiction, 1984, 79:215-9; K. O. Fagerstrom in Nicotine Replacement: a Critical Evaluation, O. F. Pomperleau and C. S. Pomperleau, eds., Alan R. Liss, Inc., New York, 1988, pp. 109-28; and J. E. Henningfield and D. R. Jasinski, ibid., pp.35-61). Irritability and impatience were reduced in at least five independent controlled studies, while anxiety and concentration difficulties were reduced in at least two studies. Other studies have shown nicotine to have been significantly more effective than a placebo in relieving depression, hunger, somatic complaints and sociability. Nicotine has also been found to be effective in reducing anger, irritability, frustration and feelings of tension, while increasing the ability to focus upon the completion of tasks, without causing general response depression, drowsiness or sedation (R. R. Hutchinson et al., U.S. Pat. No. 3,879,794, issued Mar. 11, 1975).
One approach to alleviating the symptoms of tobacco withdrawal has been to develop more efficient methods of delivering nicotine, for example, with transdermal patches (F. T. Etscorn, U.S. Pat. No. 4,597,961, issued Jul. 1, 1986). The major problem with this approach relates to the non-selective effects of nicotine upon the heart, in particular its stimulant effects in increasing cardiac workload and oxygen demand. A selective cholinergic channel activator would be expected to be equally efficacious in relieving withdrawal symptoms, but with fewer cardiovascular liabilities.
Withdrawal from addictive substances, regardless of which particular agent is withdrawn, is in general a traumatic experience characterized by anxiety and frustration. These emotional disturbances contribute to failure in therapy and, consequently, to a return to substance dependence. Although ameliorating the feelings of anger, irritability, frustration and tension, any agent improving the individual's ability to cope and to concentrate should vastly improve the chances of successfully completing withdrawal treatment even though it would not eliminate the craving for the withdrawn drug.
It has now been discovered that compounds according to this invention are selective and potent cholinergic channel activators or ligands useful in treating these problems. Additionally, one of these compounds has been shown to have analgesic properties.
Compounds with somewhat similar structures are known.
Abreo et al. (PCT application WO 94/08992, published Apr. 28, 1994) have disclosed pyrrolidine compounds of the formula: ##STR2## wherein R.sup.1 and R.sup.2 include H and C.sub.1 -C.sub.6 -alkyl, and B includes a 3-pyridinyl group further mono-substituted in a limited and specified manner with only a hydroxyl, alkyl, alkoxy, or halogen group, and have suggested these compounds as agents to enhance cognitive function.
Shanklin et al. (U.S. Pat. No. 5,130,309, issued Jul. 14, 1992) disclose 2-aryloxyalkylazetidine compounds of the formula: ##STR3## wherein R includes H and C.sub.1 -C.sub.4 -alkyl, X includes hydrogen, halogen, trifluoromethyl and C.sub.1 -C.sub.4 -alkyl, and Y is hydrogen and C.sub.1 -C.sub.4 -alkyl, and Aberg et al. (U.S. Pat. No. 4.822,778, issued Apr. 18, 1989) disclose 2-phenoxyalkylpiperidine compounds of the formula: ##STR4## wherein R.sup.1 includes hydrogen and C.sub.1 -C.sub.4 -alkyl, and R is a phenyl or cyclohexyl group optionally substituted with 1-to-4 methyl groups, each disclosing their compounds as antiarrhythmic and anticonvulsant agents.
Helsley (U.S. Pat. No. 3,577,432, issued May 4, 1971), disclosing 3-phenoxypyrrolidine compounds of the formula: ##STR5## wherein R includes C.sub.1 -C.sub.4 -alkyl, and when n is 0, phenyl, and R.sup.1 and R.sup.2 include hydrogen, halogen, lower alkoxy, acetyl and trifluoromethyl, suggests these compounds as muscle relaxant, anti-convulsive and major tranquilizing agents. Cale (U.S. Pat. No. 3,577,415, issued May 4, 1971) discloses additional 3-phenoxypyrrolidine compounds of the formula: ##STR6## wherein R includes methyl, benzyl and carbamoyl, and R.sup.1 includes carbamoyl, carboxyl, amino, aminomethyl, cyano, and acetamido, as anti-depressant agents.
Schohe et al. (U.S. Pat. No. 5,037,841, issued Aug. 6, 1991) disclose 1-substituted-3-phenoxyalkyl compounds of the formula: ##STR7## wherein A includes an optionally-substituted phenyl grouping and B includes a cyano, carboxyl, carboxyamido, sulfonamido, amino, or aminobutynyl grouping, as agents having high affinity for 5-hydroxytryptamine receptors of the 5-HT.sub.1 -type. Fujii et al. (U.S. Pat. No. 5,145,865, issued Sep. 8, 1992), disclosing N-phenyl-phenoxymethylpyrrolidine compounds of the formula: ##STR8## suggest that their compounds are hypolipidemic agents.
Testa et al. (U.S. Pat. No. 3,290,212, issued Dec. 6, 1966) disclose an N-methyl-2-phenoxymethylpyrrolidine compound of the formula: ##STR9## as an intermediate to larger benzamide-functionalized compounds. Then, Wander AG (published application DE 2,315,092, October 1970), disclosing 3-phenoxymethylpyrrolidine compounds of the formula: ##STR10## proposed its compounds as antipsychotic or muscle relaxant agents.
We have found that the novel 2-((nitro)phenoxymethyl)heterocyclic compounds of the present invention possess unexpected utility as cholinergic channel activators or ligands of the nicotinic type. These compounds are therefore useful in treating cognitive, neurological and mental disorders characterized by decreased cholinergic function, such as, for example, attention-deficit disorder, dementias, and anxiety associated with cognitive impairment and substance abuse withdrawal.
Nothing in the referenced prior art discloses or suggests that the novel compounds of the present invention would possess these activities. Furthermore, the cited references neither disclose nor suggest that a nitro-substituted analog of the inventions thereof would have any activity, including in the biological models utilized to estimate the clinical utilities of their novel compounds.